PAK6介导的ANT2磷酸化与乙酰化相互调节在前列腺癌代谢重编程中的作用及机制

PAK6 overexpression is associated with the progression of prostate cancer. Metabolic reprogramming is important in the progression of prostate cancer, but the role and mechanism of PAK6 overexpression in the metabolic reprogramming of prostate cancer is unclear. In this project, we have identified PAK6 new interactive protein -ANT2(adenine nucleotide translocase-2). It has been confirmed that both PAK6 and ANT2 expression are downregulated and ectopic expression of PAK6 phosphorylates ANT2 and promotes its acetylation following depreivation of glucose/glutamine. In addition, PAK6 may down-regulate the expression of SIRT4 by proteasome pathway and further up-regulate ANT2 protein expression. The aim of this project is to further determine the important biological function of PAK6-ANT2 signaling pathways in prostate cancer, including mitochondrial energy metabolism, release of reactive oxygen free radicals, apoptosis and tumor formation and metastasis in vivo; to explore the mechanism for PAK6 modulating ANT2 expression, including the molecular mechanism of PAK6 down-regulating SIRT4, the interaction of phosphorylation and acetylation of ANT2 by PAK6; to elucidate the correlation between the PAK6-ANT2 interaction and prostate cancer progression. Through the above studies, we will clarify the role of PAK6-ANT2 signaling pathway in the progression of prostate cancer, providing a new molecular target for the treatment of prostate cancer.

PAK6过表达与前列腺癌进程相关，代谢重编程在前列腺癌进程中具有重要意义，但PAK6过表达在前列腺癌代谢重编程中的作用及机制尚不清楚。本项目前期筛选出PAK6新的互作蛋白-ANT2。已初步证实在葡萄糖/谷氨酰胺缺失时，PAK6与ANT2表达均下调，且过表达PAK6磷酸化并上调ANT2蛋白表达，促进ANT2乙酰化。此外，PAK6可能通过蛋白酶体途径下调SIRT4表达，进一步上调ANT2蛋白表达。本课题旨在进一步确定PAK6-ANT2信号通路在前列腺癌代谢重编程中的重要生物学功能，包括对细胞线粒体能量代谢、活性氧自由基释放、细胞凋亡及小鼠体内成瘤及转移的影响；寻找PAK6上调ANT2的分子机制，包括PAK6下调SIRT4的分子机制、PAK6介导ANT2的磷酸化与乙酰化相互调节；阐明PAK6与ANT2相互作用与前列腺癌进程与预后的关系。通过上述研究，为临床前列腺癌治疗提供新的分子靶标

p21活化激酶6（PAK6）是Ⅱ类PAKs家族成员之一，是一类保守的丝氨酸/苏氨酸蛋白激酶。尽管对恶性肿瘤特别是前列腺癌中的PAK6已经进行了大量的研究，但是对于线粒体定位的PAK6在前列腺癌中的作用及机制尚不清楚。本项目揭示了线粒体内膜定位的PAK6与SIRT4和ANT2 ( 腺嘌呤核苷酸转位酶 2, 催化细胞质和线粒体间 ATP/ADP 跨膜交换) 形成复合物，参与调控前列腺癌细胞凋亡。其中PAK6促进SIRT4泛素介导的蛋白水解。此外，SIRT4去除了ANT2 K105位点的乙酰化，以促进其泛素化降解。因此，PAK6通过PAK6-SIRT4-ANT2通路调节ANT2的乙酰化水平，从而调节ANT2的稳定性。同时，PAK6直接在T107位点磷酸化ANT2 以抑制前列腺癌细胞的凋亡。因此，ANT2的磷酸化和去乙酰化修饰相互调节，促进肿瘤生长。临床前列腺癌组织评估显示PAK6与ANT2表达呈正相关，但与 SIRT4 表达呈负相关。目前的研究结果表明 PAK6-SIRT4-ANT2 复合物在前列腺癌凋亡中的关键作用，该复合物可能是前列腺癌治疗和预后的潜在生物标志物。